Cutaneous Manifestations of Systemic Disease

Panniculitis and neutrophilic dermatoses

Erythema nodosum. The most common panniculitis is a delayed hypersensitivity reaction in the subcutaneous fat. Tender, warm, red nodules appear on both anterior shins, often with fever and arthralgia, and fade through bruise-like colors over weeks without ulcerating or scarring. Biopsy shows a septal panniculitis without vasculitis. Many cases are idiopathic; identifiable triggers include streptococcal pharyngitis, sarcoidosis, inflammatory bowel disease (flaring with bowel activity), primary tuberculosis, coccidioidomycosis and histoplasmosis, oral contraceptives, sulfonamides and pregnancy. Treat the trigger and give NSAIDs and leg elevation.

Löfgren syndrome, an acute sarcoidosis with a good prognosis, combines erythema nodosum, bilateral hilar lymphadenopathy, ankle arthritis and fever.

Erythema induratum. Also called Bazin disease, this lobular panniculitis with vasculitis forms nodules on the posterior calves that ulcerate; it is classically a reaction to tuberculosis.

Pyoderma gangrenosum. A neutrophilic dermatosis in which a pustule or nodule rapidly breaks down into a painful ulcer with a purulent base and a violaceous, undermined border, usually on the legs or around a stoma; it heals with cribriform scars. Associations include IBD, rheumatoid arthritis, myeloid neoplasms (AML, MDS, myeloproliferative neoplasms) and IgA monoclonal gammopathy. It is a diagnosis of exclusion after infection, vasculitis and malignancy are ruled out, and it shows pathergy: trauma, including surgical debridement, makes it worse. Systemic glucocorticoids, cyclosporine or anti-TNF agents are used.

Sweet syndrome. Acute febrile neutrophilic dermatosis begins abruptly with fever, neutrophilia and tender, edematous red-violet plaques on the face, neck and arms. Biopsy shows a dense dermal neutrophilic infiltrate with papillary edema and no vasculitis; leukemia cutis, by contrast, shows blasts. Triggers include AML and MDS, drugs (especially G-CSF), infections, IBD and pregnancy. The response to systemic glucocorticoids is rapid and dramatic.

Endocrine and metabolic clues

Necrobiosis lipoidica. Well-demarcated, waxy yellow-brown atrophic plaques with telangiectasias and red-violet borders develop on the anterior shins, mostly in diabetes (type 1 more than type 2), and may ulcerate after minor trauma. Histology shows palisading granulomas around degenerated (necrobiotic) collagen arranged in horizontal tiers through the dermis.

Xanthomas. Every xanthoma is a dermal collection of lipid-laden foamy macrophages, but its shape and site identify the lipid disorder. Eruptive xanthomas, sudden crops of small yellow papules with red halos on the buttocks and extensor surfaces, signal severe hypertriglyceridemia (usually >1,000 mg/dL) from chylomicronemia syndromes or uncontrolled diabetes, a level that also risks pancreatitis; they fade as triglycerides fall. Tendon xanthomas mean familial hypercholesterolemia. Xanthelasma of the eyelids is the most common xanthoma and often occurs with normal lipids, although a lipid panel is warranted.

Pretibial myxedema. Graves disease can produce waxy, nonpitting, peau d'orange plaques or nodules on the shins and dorsal feet, usually alongside ophthalmopathy. TSH receptor antibodies activate dermal fibroblasts, which deposit glycosaminoglycans such as hyaluronic acid. Thyroid acropachy (clubbing with periosteal new bone) completes the triad. The generalized myxedema of hypothyroidism also reflects dermal glycosaminoglycan buildup, but it is diffuse and antibody-independent.

Porphyria cutanea tarda. The most common porphyria results from reduced hepatic uroporphyrinogen decarboxylase (UROD) activity, sporadic or inherited, unmasked by hepatitis C, alcohol, iron overload (HFE mutations), estrogens, HIV and smoking. Accumulated uroporphyrins absorb light and damage skin: painless blisters, erosions and fragility on the dorsal hands, forearms and face heal with milia and scars, with facial hypertrichosis and hyperpigmentation. Urine is tea-colored and fluoresces pink-orange under a Wood lamp. In the heme pathway, ALA synthase is rate-limiting, lead inhibits ALA dehydratase and ferrochelatase, porphobilinogen deaminase and uroporphyrinogen III cosynthase build uroporphyrinogen III, and UROD converts it to coproporphyrinogen III. Unlike acute intermittent porphyria (porphobilinogen deaminase deficiency), PCT causes no neurovisceral attacks. Management removes triggers, treats hepatitis C, and lowers iron by phlebotomy or uses low-dose hydroxychloroquine.

Calciphylaxis. Also called calcific uremic arteriolopathy, it occurs mainly in patients on dialysis with hyperphosphatemia, a high calcium-phosphate product and hyperparathyroidism; warfarin, calcium-based binders, diabetes and obesity add risk. Small dermal and subcutaneous arterioles calcify, develop intimal hyperplasia and thrombose, producing exquisitely painful retiform purpura that evolves into necrotic eschars over fatty areas such as the thighs and abdomen. Mortality is high, largely from sepsis. Care includes sodium thiosulfate, wound care, correction of calcium and phosphate, and stopping warfarin.

Signs of chronic liver disease

Hyperestrogenism. A cirrhotic liver clears estrogen poorly and more androgen is aromatized peripherally, producing spider angiomas (a central arteriole with radiating vessels that blanches when the center is pressed, found in the superior vena cava territory), palmar erythema over the thenar and hypothenar eminences, gynecomastia and testicular atrophy. Spider angiomas also appear in pregnancy.

Other clues. Jaundice, caput medusae from portal hypertension, Terry nails and excoriations from cholestatic pruritus complete the picture.

Paraneoplastic skin signs

Glucagonoma. This alpha-cell pancreatic neuroendocrine tumor causes necrolytic migratory erythema: annular, migrating red plaques with erosions, flaccid blisters and crusts in the perineum, groin, perioral skin and legs. Diabetes, DVT, weight loss, glossitis and depression accompany it, and low amino acid and zinc levels contribute to the rash.

Carcinoid syndrome. Serotonin and kinins from a midgut neuroendocrine tumor reach the systemic circulation once liver metastases bypass hepatic monoamine oxidase, causing episodic flushing of the face and upper trunk, diarrhea, wheezing and right-sided valve fibrosis. Urine 5-HIAA confirms it. Diverting tryptophan to serotonin can produce niacin deficiency: pellagra, with dermatitis on sun-exposed skin, diarrhea and dementia.

Trousseau syndrome and dermatomyositis. Recurrent migratory superficial thrombophlebitis signals an occult mucin-producing adenocarcinoma, classically pancreatic. Adult dermatomyositis (heliotrope eyelids, Gottron papules) warrants a search for cancer of the ovary, lung and GI tract, especially with anti-TIF1-γ antibodies.

Trousseau syndrome (migratory thrombophlebitis) is not Trousseau sign, the carpal spasm of hypocalcemia provoked by an inflated blood pressure cuff.

Skin clues to infection

Endocarditis. Janeway lesions are painless, flat, hemorrhagic macules on the palms and soles caused by septic microemboli with microabscesses, classically in acute Staphylococcus aureus endocarditis. Osler nodes are painful, raised violaceous nodules on the pads of the fingers and toes caused by immune-complex deposition, classically in subacute viridans streptococcal disease. Septic pulmonary emboli and splenic infarcts are embolic as well.

Ecthyma gangrenosum. Pseudomonas aeruginosa bacteremia in neutropenic or otherwise immunocompromised patients invades the walls of dermal vessels, causing thrombosis. The lesion evolves from a painless red macule to a hemorrhagic bulla to a necrotic ulcer with a black eschar and red halo, often in the perineum, axilla or limbs. Draw blood cultures and start antipseudomonal antibiotics urgently.